U.S. patent number 11,117,895 [Application Number 16/297,550] was granted by the patent office on 2021-09-14 for process for producing crystals of a diazabicyclooctane derivative.
This patent grant is currently assigned to MEIJI SEIKA PHARMA CO., LTD.. The grantee listed for this patent is MEIJI SEIKA PHARMA CO., LTD.. Invention is credited to Shusuke Furuyama, Kenichi Fushihara, Masato Ichiki, Takaya Ogawa, Takuya Yokoyama.
United States Patent |
11,117,895 |
Ogawa , et al. |
September 14, 2021 |
Process for producing crystals of a diazabicyclooctane
derivative
Abstract
A process for producing crystals of a compound represented by
the following formula (I): ##STR00001## by crystallizing the
compound from an aqueous solution containing the compound and an
inorganic salt, such as sodium chloride. Such crystals can be
subjected to lyophilization to provide a lyophilized composition
having a desirable storage stability.
Inventors: |
Ogawa; Takaya (Kanagawa,
JP), Yokoyama; Takuya (Kanagawa, JP),
Furuyama; Shusuke (Kanagawa, JP), Ichiki; Masato
(Kanagawa, JP), Fushihara; Kenichi (Kanagawa,
JP) |
Applicant: |
Name |
City |
State |
Country |
Type |
MEIJI SEIKA PHARMA CO., LTD. |
Tokyo |
N/A |
JP |
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Assignee: |
MEIJI SEIKA PHARMA CO., LTD.
(Tokyo, JP)
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Family
ID: |
1000005800616 |
Appl.
No.: |
16/297,550 |
Filed: |
March 8, 2019 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20190202831 A1 |
Jul 4, 2019 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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15532281 |
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10294224 |
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PCT/JP2015/084094 |
Dec 4, 2015 |
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Foreign Application Priority Data
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Dec 5, 2014 [JP] |
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2014-246425 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D
471/08 (20130101); A61K 31/439 (20130101); A61K
9/19 (20130101); A61K 9/0019 (20130101); A61K
47/02 (20130101); C07B 2200/13 (20130101) |
Current International
Class: |
C07D
471/08 (20060101); A61K 9/00 (20060101); A61K
47/02 (20060101); A61K 9/19 (20060101); A61K
31/439 (20060101) |
References Cited
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WO |
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Apr 2015 |
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WO |
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|
Primary Examiner: O'Dell; David K
Attorney, Agent or Firm: Holtz, Holtz & Volek PC
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a Divisional application of U.S. application
Ser. No. 15/532,281, filed Jun. 1, 2017, which is a U.S. National
Phase application of International Application No.
PCT/JP2015/084094, filed Dec. 4, 2015, which is based upon and
claims the benefit of priority from prior Japanese Patent
Application No. 2014-246425, filed Dec. 5, 2014. The entire
contents of all the above-identified applications are incorporated
herein by reference.
Claims
The invention claimed is:
1. A process for producing crystals of a compound represented by
the following formula (I): ##STR00007## comprising crystallizing
the compound from an aqueous solution containing the compound and
an inorganic salt, without previous purification of the compound
with a column, wherein a crystalline form I of the compound having
characteristic peaks appearing at a lattice spacing (d) of 7.34,
5.66, 5.53, 5.30, 5.02, 4.66, 4.37, 4.28, 4.06, 3.68, 3.62, 3.47,
3.36, 3.30, 3.16, 3.11, 3.03, 2.99 and 2.50 .ANG. in a powder X-ray
diffraction pattern is produced.
2. A process for producing crystals of a compound represented by
the following formula (I): ##STR00008## comprising crystallizing
the compound from an aqueous solution containing the compound and
an inorganic salt, without previous purification of the compound
with a column, wherein the aqueous solution containing the compound
and an inorganic salt is obtained by dissolving the compound and
the inorganic salt together in water, or by dissolving either of
the compound or the inorganic salt in water and then dissolving the
other in the resultant solution, and wherein a crystalline form I
of the compound having characteristic peaks appearing at a lattice
spacing (d) of 7.34, 5.66, 5.53, 5.30, 5.02, 4.66, 4.37, 4.28,
4.06, 3.68, 3.62, 3.47, 3.36, 3.30, 3.16, 3.11, 3.03, 2.99 and 2.50
.ANG. in a powder X-ray diffraction pattern is produced.
3. A process for producing crystals of a compound represented by
the following formula (I): ##STR00009## comprising crystallizing
the compound from an aqueous solution containing the compound and
an inorganic salt, without previous purification of the compound
with a column, wherein the compound is crystallized by adding a
poor solvent to the aqueous solution containing the compound and
the inorganic salt, and wherein a crystalline form I of the
compound having characteristic peaks appearing at a lattice spacing
(d) of 7.34, 5.66, 5.53, 5.30, 5.02, 4.66, 4.37, 4.28, 4.06, 3.68,
3.62, 3.47, 3.36, 3.30, 3.16, 3.11, 3.03, 2.99 and 2.50 .ANG. in a
powder X-ray diffraction pattern is produced.
4. The process according to claim 3, wherein the poor solvent is an
alcohol.
5. The process according to claim 1, wherein the compound is
crystallized by subjecting the aqueous solution containing the
compound and the inorganic salt to lyophilization.
Description
TECHNICAL FIELD
The present invention relates to a process for producing crystals
of a diazabicyclooctane derivative represented by formula (I), as
well as a composition and lyophilized preparation of said
derivative, and a process for producing the same.
BACKGROUND
The novel diazabicyclooctane derivative represented by formula (I)
below:
(2S,5R)--N-(2-aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo
[3.2.1]octane-2-carboxamide (hereinafter referred to as "Compound
(I)") is a .beta.-lactamase inhibitor, and disclosed in
WO2013/180197 (Patent Document 1).
##STR00002##
A method for obtaining a crystalline lyophilized composition has
been disclosed in which a solution of a chemical substance is
frozen at a prescribed temperature, and heated to a prescribed
temperature, after which the temperature is kept constant
(hereafter referred to as a heat treatment step) (Patent Document
2).
Patent Document 3 and Patent Document 4 disclose that an inorganic
salt may be added to an solution of a chemical substance in
lyophilization methods that involve a heat treatment step.
Patent Document 5 discloses a method for obtaining a crystalline
lyophilized composition by subjecting an aqueous solution of a
chemical substance containing 2 to 10% (v/v) of a C.sub.1-3 alcohol
or acetone to a lyophilization procedure that involves a heat
treatment step.
Patent Document 6 discloses crystals of compound (I) and production
process thereof.
PRIOR ART DOCUMENTS
Patent Documents
[Patent Document 1] WO2013/180197 [Patent Document 2] Japanese
Examined Patent Publication No. Hei 03-74643 [Patent Document 3]
Japanese Patent No. 2843444 [Patent Document 4] Japanese Patent No.
2767171 [Patent Document 5] Japanese Examined Patent Publication
No. Sho 60-19759 [Patent Document 6] WO 2015/053297
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
Our studies have shown that when compound (I) is lyophilized using
standard conditions that include a freezing step, followed by a
step of drying under reduced pressure, compound (I) becomes
amorphous, and that its chemical stability is significantly lower
than the crystalline state, making it difficult to obtain a
lyophilized composition having good storage stability. In light of
producing and distribution, a stable lyophilized composition of
compound (I) has been highly sought after.
However, lyophilization of an aqueous solution of compound (I)
using the method of Patent Document 2 did not yield a crystalline
lyophilized composition. The examples of Patent Document 3 show
that a crystalline lyophilized composition can be obtained whether
or not an inorganic salt is added, which means that addition of an
inorganic salt is not essential for crystallization. Moreover, it
is disclosed that, under standard lyophilization conditions that
involve no heat treatment step, addition of an inorganic salt leads
to an increase in amorphous content, thereby adversely affecting
crystallization. Furthermore, in Patent Document 4, a heat
treatment step is incorporated without exception and there are no
examples where an inorganic salt is added. The method of Patent
Document 5 is not desirable as an industrial producing process, as
there is concern over residual solvents.
As seen from the above, no methods have been found for obtaining a
crystalline lyophilized composition under lyophilization conditions
that do not involve a heat treatment step or addition of an organic
solvent.
On the other hand, the process of Patent Document 6 could not
provide crystals of compound (I) sufficiently before an aqueous
solution containing compound (I) is purified once by a column and
the like.
Further, it is problem to obtain a single crystalline form and in
particular stable form I by controlling polymorphism.
Therefore, a process for producing crystals of compound (I) easily
in an industrial scale, and further a process for producing a
single crystalline form and in particular crystalline form I of
compound (I) has been highly sought after.
The objects of the present invention are to provide a process for
producing crystals, especially a single crystalline form and in
particular stable crystalline form I of compound (I) easily in an
industrial scale, and a stable lyophilized composition of compound
(I).
Means for Solving the Problems
As a result of extensive research on developing a lyophilized
composition of compound (I) having good storage stability, the
present inventor has found that subjecting an aqueous solution
containing compound (I) and an inorganic salt such as sodium
chloride to lyophilization crystallizes the compound (I), and
consequently yields a lyophilized composition having good storage
stability wherein the compound (I) is crystalline, especially a
single crystalline form and in particular stable crystalline form
I, and has further found that crystals, especially a single
crystalline form and in particular stable crystalline form I of
compound (I) can be obtained from said aqueous solution without
lyophilization, thereby completing the present invention.
The present invention relates to a process for producing crystals
of compound (I), comprising crystallizing compound (I) from an
aqueous solution containing compound (I) and an inorganic salt such
as sodium chloride.
The present invention also relates to a process for producing a
lyophilized composition comprising compound (I), comprising
crystallizing compound (I) by said process for producing crystals
of compound (I); a process for producing a lyophilized composition
comprising compound (I), comprising crystallizing compound (I) by
subjecting an aqueous solution containing compound (I) and an
inorganic salt such as sodium chloride to lyophilization; as well
as a lyophilized composition containing crystals of compound (I)
and an inorganic salt such as sodium chloride. The lyophilized
composition of the present invention is obtainable by said process
for producing a lyophilized composition.
In the present invention, for example, compound (I) is crystallized
by a general method including a method wherein a seed crystal is
added as necessary to an aqueous solution containing compound (I)
and an inorganic salt such as sodium chloride, and then a poor
solvent is added thereto. Or, compound (I) is crystallized by
subjecting an aqueous solution containing compound (I) and an
inorganic salt such as sodium chloride to lyophilization. The
presence of an inorganic salt such as sodium chloride allows
crystals of compound (I), especially, same crystalline form I as
one disclosed in Patent Document 6 to be obtained, thereby
drastically improving storage stability compared to amorphous
states.
Crystalline form I of the present invention is the same as
crystalline form I of Patent Document 6, and shows a characteristic
peak pattern in powder X-ray diffraction as shown in Table 1 and
FIG. 3 below. In the present invention, the powder X-ray
diffraction is measured according to a method mentioned in Test
example 1.
TABLE-US-00001 TABLE 1 Powder X-ray data Powder X-ray diffraction
of Crystalline form I Peak position 2.theta. Latticer spacing (d)
Relative intensity (CuK.alpha.) .ANG. I/IO 12.04 7.34 13 15.64 5.66
53 16.02 5.53 26 16.70 5.30 58 17.66 5.02 49 19.02 4.66 100 20.30
4.37 46 20.74 4.28 11 21.88 4.06 10 24.16 3.68 11 24.56 3.62 15
25.66 3.47 18 26.54 3.36 17 26.96 3.30 13 28.18 3.16 12 28.72 3.11
14 29.44 3.03 16 29.86 2.99 13 35.90 2.50 10
Further, in the present invention, an aqueous solution containing
compound (I) and an inorganic salt such as sodium chloride is
subjected to lyophilization. For example, it is lyophilized using
standard conditions that include a freezing step, and a subsequent
step of drying under reduced pressure. That is, the present
invention also relates to a process for producing a lyophilized
composition comprising compound (I), comprising subjecting an
aqueous solution containing compound (I) and an inorganic salt such
as sodium chloride to a freezing step, and subjecting a frozen
product obtained in said freezing step to a step of drying under
reduced pressure. The presence of an inorganic salt such as sodium
chloride allows a lyophilized composition to be obtained wherein
the compound (I) is crystalline and especially crystalline form I,
thereby drastically improving storage stability compared to
amorphous states.
In the present invention, a lyophilized composition wherein the
compound (I) is crystalline can be obtained without involving a
heat treatment step or a refreezing step between the steps of
freezing and drying under reduced pressure. That is, in the process
of the present invention for producing a lyophilized composition,
no heat treatment or refreezing of a frozen product obtained in
said freezing step may be performed. In general, lyophilization is
a producing process that requires a long time. Methods are known
for obtaining a crystalline lyophilized composition that involve a
heat treatment step and a refreezing step between the steps of
freezing and drying under reduced pressure, but there is a problem
of low productivity due to further extended producing times. In the
present invention, a lyophilized composition wherein the compound
(I) is crystalline can be obtained without involving a heat
treatment step or a refreezing step between the steps of freezing
and drying under reduced pressure, thereby increasing productivity
compared to conventional methods.
In the present invention, a heat treatment step and a refreezing
step may be incorporated between the steps of freezing and drying
under reduced pressure. That is, the present invention also relates
to said process for producing a lyophilized composition comprising
compound (I), further comprising subjecting the frozen product
obtained in said freezing step to a heat treatment step, subjecting
a heat-treated product obtained in said heat treatment step to a
refreezing step, and subjecting a refrozen product obtained in said
refreezing step to said step of drying under reduced pressure. The
incorporation of a heat treatment step further improves the
crystallization efficiency of compound (I).
Effects of Invention
In the present invention, crystals of compound (I) can be obtained
by crystallization from an aqueous solution containing compound (I)
and an inorganic salt without previous purification of compound (I)
with a column, etc., and thus, crystals, especially a single
crystalline form and in particular stable crystalline form I of
compound (I) can be predominantly produced easily in an industrial
scale. Further, in the present invention, a lyophilized composition
wherein compound (I) is crystalline, especially a single
crystalline form and in particular crystalline form I can be
obtained by lyophilization from an aqueous solution containing
compound (I) and an inorganic salt, and then a lyophilized
preparation of compound (I) having good storage stability can be
provided.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 Powder X-ray diffractogram of the lyophilized composition
obtained in Example 1a.
FIG. 2 Powder X-ray diffractogram of the lyophilized composition
obtained in Example 1b.
FIG. 3 Powder X-ray diffractogram of the crystals obtained in
Example 2b.
FIG. 4 Powder X-ray diffractogram of the lyophilized composition
obtained in Comparative example 1.
FIG. 5 Powder X-ray diffractogram of sodium chloride.
MODE FOR CARRYING OUT THE INVENTION
Any inorganic salt that can be added to a parenteral injection may
be used in the present invention, and sodium chloride, magnesium
chloride, calcium chloride, potassium chloride, ammonium chloride,
sodium bromide, calcium bromide, potassium bromide, tetrabutyl
ammonium bromide, magnesium sulfate, sodium iodide, potassium
iodide, sodium hydrogenphosphate, sodium acetate, sodium citrate,
sodium tartrate, sodium glutamate, Rochelle salt (potassium sodium
tartrate), etc. are exemplified. Sodium chloride, magnesium
chloride, magnesium sulfate, sodium citrate, sodium glutamate and
Rochelle salt (potassium sodium tartrate) are preferable in terms
of crystallization efficiency. It was confirmed that crystalline
form I of compound (I) can be obtained by using any of these
inorganic salts. Sodium chloride is particularly preferable. The
amount of the inorganic salt of the present invention contained in
a lyophilized composition or a medicinal preparation may vary, but
is preferably 0.1 to 10 molar equivalents, and more preferably 1 to
2 molar equivalents to compound (I). This is because adding the
amount that is too large or too small would result in a decrease in
crystallization efficiency, and affect the stability of the
preparation.
Further, in case of crystallization from an aqueous solution
containing compound (I) and an inorganic salt, the amount of the
inorganic salt contained in said aqueous solution may vary, but is
preferably 0.1 to 10 molar equivalents, and more preferably 0.5 to
1.5 molar equivalents to compound (I).
In the present invention, the concentration of compound (I) in the
aqueous solution prior to crystallization or lyophilization is
typically 1 to 40% (w/w), preferably 2.5 to 20% (w/w), and more
preferably 7.5 to 10% (w/w). This is because low said
concentrations lead to a decrease in crystallization efficiency,
thereby affecting the stability of the preparation, whereas high
said concentrations are prone to precipitation from oversaturated
solutions.
An aqueous solution containing compound (I) and an inorganic salt
of the present invention may be prepared by dissolving compound (I)
and an inorganic salt together in water, or by dissolving either of
them in water to provide a solution, and then dissolving the
residual other in the solution
In the present invention, for example, compound (I) is crystallized
by adding a seed crystal as necessary to an aqueous solution
containing compound (I) and an inorganic salt, and then adding a
poor solvent thereto. Here, as the seed crystal, seed crystals of
compound (I) may be used, for example, crystalline forms I of
Patent Document 6 may be used. Or, a lyophilized composition
obtained by subjecting an aqueous solution containing compound (I)
and an inorganic salt to lyophilization may be used as the seed
crystal. The amount of the seed crystal used is 0 to 20 wt % and
preferably 0.01 to 2 wt %.
Examples of poor solvents include alcohol such as methanol, ethanol
1-propanol and isopropanol, acetone, acetonitrile, and
tetrahydrofuran, and preferably include alcohol such as methanol,
ethanol, 1-propanol or isopropanol. The amount of the poor solvent
is adjusted based on solubility so that isolation loss is 1% or
less. For example, the poor solvent is used at 1 to 10 times,
preferably 3 to 7.5 times and more preferably 5 to 7.5 times, the
initial volume of the aqueous solution containing compound (I) and
an inorganic salt. The timing of the addition of poor solvent is
not limited. For example, after the mixture has formed slurry
following seeding, the poor solvent is dropped therein in the case
of crystalline form I. Time for the addition of poor solvent is not
limited, and for example, half an hour or more, and preferably one
hour or more.
In the present invention, compound (I) may be crystallized after
control of the temperature of an aqueous solution containing
compound (I) and an inorganic salt.
Stirring time is dependent upon precipitation rate, and stirring is
carried out for 1 hour to 24 hours and preferably for 1 hour to 15
hours.
The crystals of compound (I) can be obtained by ordinary
filtration, washing and through-flow drying or vacuum drying of the
precipitated crystals. In the case of solvated crystals, excessive
drying is avoided by using means to controlling material
temperature, loss on drying, humidified and limited vacuum drying
or humidified through-flow drying.
In the present invention, compound (I) may be crystallized by
subjecting an aqueous solution containing compound (I) and an
inorganic salt to lyophilization. Further, the present invention
also relates to a process for producing a lyophilized composition
comprising compound (I), comprising crystallizing compound (I) by
subjecting an aqueous solution containing compound (I) and an
inorganic salt to lyophilization.
In the present invention, for example, an aqueous solution
containing compound (I) and an inorganic salt is subjected to a
conventional lyophilization procedure that includes a freezing step
and a step of drying under reduced pressure. The refrigeration
temperature used for freezing said aqueous solution varies
depending on the concentrations of compound (I) and the inorganic
salt, but is typically between -60 and -10.degree. C., preferably
between -50 and -10.degree. C., more preferably between -50 and
-15.degree. C. The rate used for freezing may vary, but the
freezing step typically lasts for 0.25 to 5 hours. After freezing,
the frozen product obtained in the freezing step may be stored at
the refrigeration temperature for a period of time until the next
step of drying under reduced pressure.
The step of drying under reduced pressure to which the frozen
product obtained in said freezing step is subjected may be divided
into a step of primary drying (sublimation) and a step of secondary
drying (dehumidification). The primary drying step is performed, as
is typical, under reduced pressure, and although the temperature to
be used cannot be specified because it is affected by the
concentrations of compound (I) and an inorganic salt, it is
preferably adjusted to conditions in which the temperature of the
material does not exceed the collapse temperature of the frozen
product. The drying time cannot be specified because it varies
depending on the temperature used and the scale of production, but
this step may typically last for 2 hours to 7 days, preferably 5
hours to 72 hours, while changes in the temperature of the material
and the degree of vacuum are monitored. The secondary drying step
is performed, as is typical, under reduced pressure and it may be
performed at a temperature of, for example, 10 to 60.degree. C.,
preferably 25 to 60.degree. C. The drying time cannot be specified
because it varies depending on the temperature used and the scale
of production, but this step may typically last for 2 to 72 hours,
preferably 5 to 20 hours, while changes in the temperature of the
material and the degree of vacuum are monitored.
In the present invention, to improve crystallization efficiency, a
heat treatment step and a refreezing step may be incorporated
between the freezing step and the step of drying under reduced
pressure, which are described above. The temperature used in heat
treatment of the frozen product obtained in said freezing step is
affected by the concentrations of compound (I) and an inorganic
salt, but this step is performed at a temperature where the
material remains frozen, preferably at -40 to 0.degree. C., and
more preferably -20 to -4.degree. C. The heat treatment time cannot
be specified because it varies depending on the temperature used
and the scale of production, but this step may typically last for
0.5 to 72 hours, preferably 1 to 24 hours. The temperature used in
the refreezing step to which a heat-treated product obtained in
said heat treatment step is subjected is typically -60 to
-10.degree. C., preferably -50 to -10.degree. C., more preferably
-50 to -15.degree. C. The freezing rate may vary, but this step
typically lasts for 0.25 to 5 hours. A refrozen product obtained in
the refreezing step is subjected to said step of drying under
reduced pressure.
When the crystals and the lyophilized compositions of the present
invention are used as a medicament, they may be administered as
such (as ingredients), or may be administered as a conventional
medicinal preparation. Said medicinal preparation may contain a
pharmacologically acceptable additive such as excipient, lubricant,
binder, disintegrant, emulsifier, stabilizer, flavoring agent,
diluent or the like, so long as the additive do not undermine the
effects of the present invention. Examples of said medicinal
preparation include tablets, capsules, powders, syrups, granules,
fine granules, pills, suspensions, emulsions, percutaneous
absorption preparations, suppositories, ointments, lotions,
inhalants, injections and the like. The crystals and the
lyophilized compositions of the present invention as well as said
medicinal preparation may be orally or parenterally administered
(such as intravenous administration, intramuscular administration,
intraperitoneal administration, percutaneous administration,
intratracheal administration, intracutaneous administration, or
subcutaneous administration).
In said medicinal preparation of the present invention, in addition
to compound (I), a .beta.-lactamase inhibitor, .beta.-lactam
antibiotics may be incorporated. Examples of what may be
incorporated include piperacillin, ampicillin, benzylpenicillin,
cefoperazone, cefazolin, cefalotin, cefotiam, cefminox,
cefmetazole, flomoxef, cefodizime, cefotaxime, ceftriaxone,
cefmenoxime, latamoxef, ceftazidime, cefepime, cefozopran,
cefpirome, aztreonam, imipenem, doripenem, panipenem, biapenem,
meropenem, and their pharmacologically acceptable salts and
solvates.
Any additive that can generally be added to injections may, where
appropriate, be incorporated in said injections of the present
invention. Examples of what may be incorporated for the purpose of
adjusting pH include inorganic acids such as hydrochloric acid and
phosphoric acid, and salts thereof, organic acids such as citric
acid, malic acid, tartaric acid, and succinic acid, and salts
thereof, amino acids such as arginine, alanine, aspartic acid,
histidine, and glycine, and bases such as sodium hydroxide and
sodium bicarbonate. Examples of what may be incorporated for the
purpose of adjusting osmotic pressure include glucose, mannitol,
xylitol, sorbitol, sucrose, lactose, maltose, trehalose, and
dextran. Furthermore, examples of what may be incorporated for the
purpose of improving solubility include polyols such as
polyethylene glycol and glycerin, and surfactants such as
polysorbates, sorbitan sesquioleate,
polyoxyethylene-polyoxypropylene glycols, and polyoxyethylene
hydrogenated castor oils.
EXAMPLES
The following Examples and Comparative examples describe
embodiments of the present invention in concrete terms, but are not
to be construed as limiting the present invention.
Example 1
A Lyophilized Composition of Compound (I)
Example 1a
700 mg of compound (I) and 126.1 mg of sodium chloride were
dissolved into distilled water, and the total weight was adjusted
to 7 g. The solution was filtered through a 0.20-.mu.m membrane
filter (MILLEX (trademark) LG SLLGH13NH; Merck Millipore) and
placed in an amount of 1 g into a 5-mL glass vial, and then half
stoppering was performed with a rubber top. The vial filled with
the solution was set inside a lyophilizer (DFM-05B-S; ULVAC) and
cooled under atmospheric pressure for 1 hour, with the shelf
temperature of the lyophilizer set to 5.degree. C. Afterward, the
shelf temperature of the lyophilizer was lowered to -40.degree. C.
over a 1 hour period, thereby causing the solution to freeze, and
this temperature was maintained for 3 hours. Subsequently, the
pressure inside the lyophilizer was set to approximately 10 Pa, and
the shelf temperature of the lyophilizer was raised to -10.degree.
C. over a 6 hour period, after which this state was maintained for
30 hours. The pressure inside the lyophilizer was then set below 10
Pa, the shelf temperature of the lyophilizer was raised to
25.degree. C. over a 7 hour period, and this state was maintained
for 15 hours. After completion of drying, the pressure inside the
lyophilizer was reverted to atmospheric pressure using nitrogen
gas, and full stoppering was performed with a rubber top. The vial
was taken out of the lyophilizer, and an aluminum cap was screwed
on to obtain a lyophilized composition in which compound (I) is
crystalline form I. It may be added that the sodium chloride used
was of special grade and was purchased from Nacalai Tesque.
Example 1b
600 mg of compound (I) and 129.7 mg of sodium chloride were
dissolved into distilled water, and the total weight was adjusted
to 6 g. The solution was filtered through a 0.20-.mu.m membrane
filter (MILLEX (trademark) LG SLLGH13NH; Merck Millipore) and
placed in an amount of 1 g into a 5-mL glass vial, and then half
stoppering was performed with a rubber top. The vial filled with
the solution was set inside a lyophilizer (Console 12-3-ST-CR;
VirTis) and cooled under atmospheric pressure for 1 hour, with the
shelf temperature of the lyophilizer set to 5.degree. C. Afterward,
the shelf temperature of the lyophilizer was lowered to -40.degree.
C. over a 2.5 hour period, thereby causing the solution to freeze,
and this temperature was maintained for 1 hour. Subsequently, the
shelf temperature of the lyophilizer was raised to -4.degree. C.
over a 0.5 hour period, and this temperature was maintained for 15
hours. The shelf temperature of the lyophilizer was then lowered to
-40.degree. C. over a 2 hour period, thereby causing the solution
to freeze again, and this temperature was maintained for 0.5 hours.
Subsequently, the pressure inside the lyophilizer was set below 10
Pa, the shelf temperature of the lyophilizer was raised to
-10.degree. C. over a 0.5 hour period, and this state was
maintained for 20 hours. The shelf temperature of the lyophilizer
was then raised to 25.degree. C. over a 0.5 hour period, and this
state was maintained for 3 hours. After completion of drying, the
pressure inside the lyophilizer was reverted to atmospheric
pressure and full stoppering was performed with a rubber top. The
vial was taken out of the lyophilizer, and an aluminum cap was
screwed on to obtain a lyophilized composition in which compound
(I) is crystalline form I.
Example 2
Crystalline form I of Compound (I)
Example 2a
1.0 g of crystalline form III of compound (I) was dissolved in 10
mL of deionized water. 0.18 g of sodium chloride was added to the
obtained solution and dissolved therein at ambient temperature.
This solution was cooled to 0.degree. C. and then finely filtered.
To the filtrate was added dropwise 45 mL of chilled isopropanol for
over 1 hour, followed by stirring overnight. The resulted crystals
were isolated, and dried under reduced pressure at ambient
temperature for 0.5 hour to afford 0.82 g of crystals of compound
(I) (yield=82.0%, crystalline form I).
Example 2b
After dissolving 1.71 g of sodium chloride in 100 mL of deionized
water, 10 g of compound (I) was added and dissolved at ambient
temperature. This solution was cooled to 0 to 5.degree. C. and
finely filtered. Then, to the filtrate 50 mg (0.5 wt %) of
crystalline form I of compound (I) obtained in Example 2a was added
and stirred for 1 hour at 0 to 5.degree. C. 500 mL of chilled
isopropanol was added dropwise for over 1 hour, stirred overnight,
and then crystals were isolated. The obtained crystals were dried
under reduced pressure at ambient temperature for 0.5 hour to
afford 9.53 g of crystals of compound (I) (yield=94.8%, crystalline
form I).
Comparative Example 1
A Lyophilized Composition of Compound (I)
This comparative example was prepared using the same procedure as
Example 1 except that no sodium chloride was incorporated.
Specifically, 700 mg of compound (I) was dissolved into distilled
water, and the total weight was adjusted to 7 g. The solution was
filtered through a 0.20-.mu.m membrane filter (MILLEX (trademark)
LG SLLGH13NH; Merck Millipore) and placed in an amount of 1 g into
a 5-mL glass vial, and then half stoppering was performed with a
rubber top. The vial filled with the solution was set inside a
lyophilizer (DFM-05B-S; ULVAC) and cooled under atmospheric
pressure for 1 hour, with the shelf temperature of the lyophilizer
set to 5.degree. C. Afterward, the shelf temperature of the
lyophilizer was lowered to -40.degree. C. over a 1 hour period,
thereby causing the solution to freeze, and this temperature was
maintained for 3 hours. Subsequently, the pressure inside the
lyophilizer was set to approximately 10 Pa, the shelf temperature
of the lyophilizer was raised to -10.degree. C. over a 6 hour
period, and this state was maintained for 30 hours. The pressure
inside the lyophilizer was then set below 10 Pa, the shelf
temperature of the lyophilizer was raised to 25.degree. C. over a 7
hour period, and this state was maintained for 15 hours. After
completion of drying, the pressure inside the lyophilizer was
reverted to atmospheric pressure using nitrogen gas, and full
stoppering was performed with a rubber top. The vial was taken out
of the lyophilizer, and an aluminum cap was screwed on to obtain a
lyophilized composition in which compound (I) is amorphous.
Comparative Example 2
Crystalline Form I of Compound (I) (a Producing Method Using an
Octadecylsilica Gel or Resin Column Purification)
Comparative Example 2a
A 0.5 M acetate buffer (pH 5.5, 35 mL) was ice-cooled, and to this
were added compound (I) (36 g) and cooled 5M aqueous sodium
hydroxide solution alternately to adjust the pH to 5.5. The mixture
was subjected to octadecylsilica gel column chromatography (3.6 L)
and eluted with water. Active fractions were collected and
concentrated under reduced pressure with a water bath of 35.degree.
C. The precipitated crystals were dried in vacuo overnight. 2.10 g
of the resulting crystals was pulverized, and then
isopropanol/water (19/1, 13 mL) was added under ice-cooling,
followed by stirring at 0.degree. C. for 1 hour. The suspension was
filtered, followed by washing with cooled isopropanol/water (19/1,
80 mL). The resulting crystals were dried in vacuo to afford 1.68 g
of crystalline form I of compound (I) (yield 80%). DSC endothermic
peak: 111.degree. C. Solubility in an aqueous 60% isopropanol
solution: 0.44% (10.degree. C.), 0.48% (20.degree. C.).
Comparative Example 2b
Compound (I) (net 4.253 g) was dissolved in a 0.2 M phosphate
buffer (pH 6.5, 73 mL) and the pH was adjusted to 5.5, followed by
dilution with water (20 mL). The mixture was concentrated to 130
mL, subjected to resin purification (SP207, 260 mL), and eluted
with water (238 mL) and an aqueous 10% isopropanol solution (780
mL). Active fractions were collected and concentrated to 30 mL
under reduced pressure. To this was introduced activated carbon
(Seisei Shirasagi, 87 mg), followed by stirring at room temperature
for 30 minutes. The activated carbon was filtered off with a
membrane filter, and the filtrate was subjected to lyophilization
to afford 4.07 g of compound (I) in an amorphous form (yield
95.7%). This amorphous compound (I) (0.2 g) was dissolved in water
(0.8 mL), and the solution was added isopropanol (1.2 mL) and
seeded with crystalline form I (Comparative example 2a, 1 mg) at
room temperature, followed by stirring with a stirring bar for 3
hours. The precipitated crystals were filtered and dried to afford
0.1 g of crystalline form I of compound (I) (yield 50%).
Comparative Example 2c
Compound (I) (net 2.113 g) and a 0.2 M phosphate buffer (pH 6.5, 73
mL) were added alternately, and the pH was adjusted to 4.6,
followed by dilution with water (27 mL). The mixture was
concentrated to 80 mL under reduced pressure, and then the pH was
adjusted to 5.4 with a 0.2 M phosphate buffer (pH 6.5, 16 mL),
followed by dilution with water (48 mL). The mixture was subjected
to resin purification (SP207, 240 mL), and eluted with water (276
mL) and an aqueous 10% isopropanol solution (720 mL). Active
fractions were collected and concentrated under reduced pressure to
12 mL. To this was added activated carbon (Seisei Shirasagi, 40
mg), followed by stirring at room temperature for 30 minutes. The
activated carbon was filtered off through a membrane filter,
followed by dilution with water to 14 mL. The aqueous solution was
seeded with crystalline form I (Example 2b, 6 mg), stirred with a
stirring bar at room temperature. To the resulting suspension was
added dropwise isopropanol (84 mL) over 1 hour. After completion of
dropwise addition, the mixture was stirred for 3 hours. The
precipitated crystals were filtered and dried to afford 1.834 g of
crystalline form I of compound (I) (yield 86.8%). Water content:
5.37%, the content of anhydrous product: 95.3%, HPLC area ratio of
99.3%.
Test Example 1
Powder X-ray Diffraction Measurements
Powder X-ray diffraction measurements were performed for the
lyophilized compositions obtained in Example 1a, Example 1b and
Comparative example 1, the crystals obtained in Example 2a and
Example 2b, the crystals obtained in Comparative Example 2a,
Comparative Example 2b and Comparative Example 2c, and sodium
chloride using a powder X-ray diffractometer (RINT2200; Rigaku),
under the following conditions.
<Measurement Conditions>
X-ray: Cu (40 kV, 40 mA) Sample rotation: 60 rpm Divergence slit:
0.5.degree. Scattering slit: 0.5.degree. Receiving slit: 0.3 mm
Monochromator receiving slit: 0.8 mm Sampling width: 0.02.degree.
Detector: scintillation counter Scanning speed: 1.degree./min
Scanning range: 5.degree.-40.degree.
The X-ray diffractograms for Example 1a, Example 1b, Example 2b,
Comparative example 1 and sodium chloride are shown in FIGS. 1, 2,
3, 4 and 5, respectively. The lyophilized compositions obtained in
Examples 1a and 1b were crystalline while the lyophilized
composition obtained in Comparative example 1 was amorphous.
Further, it was confirmed that the crystals of Example 2b were
crystalline form I of compound (I) in view of the X-ray
diffractgram thereof. Likely, it was confirmed that the crystals of
Example 2a and Comparative examples 2a to 2c were also crystalline
form I of compound (I) in view of the X-ray diffractograms thereof,
but the data were not shown.
Considering that the same crystalline form I of compound (I) were
obtained in any of Examples 2a and 2b as well as Comparative
examples 2a to 2c, it was demonstrated that crystalline form I can
be predominantly produced by crystallization from an aqueous
solution containing sodium chloride without passing through
purification with octadecylsilica gel column chromatography or
resin performed in Comparative examples 2a to 2c.
A peak was observed at 31 to 32.degree. in the X-ray diffractograms
for Examples 1a and 1b, but the peak was absent in Example 2b.
Considering that a peak was observed at 31 to 32.degree. in the
X-ray diffractogram for sodium chloride (FIG. 5), it is understood
that this peak was caused by sodium chloride contained in the
lyophilized compositions. Since an aqueous solution containing
compound (I) and an inorganic salt is lyophilized in the present
invention, the obtained lyophilized composition obviously contains
the inorganic salt. Since the pattern except the peak at
31-32.degree. of the X-ray diffractogram for Examples 1a and 1b
matches the pattern of Example 2b, it was confirmed that crystals
obtained in Examples 1a and 1b were also crystalline form I. On the
other hand, after checking amounts of sodium ion and chloride ion
contained in crystalline form I obtained in Example 2b with ion
chromatography, both of the amounts were 0.1% or less.
In the present invention, although compound (I) is crystallized
from an aqueous solution containing compound (I) and an inorganic
salt, it was confirmed that the obtained crystals of compound (I)
does not contain the inorganic salt.
Test Example 2
Stability Evaluation
The crystals obtained in Examples 1a and 1b, and the amorphous
lyophilized composition obtained in Comparative example 1 were
subjected to stress tests at 60.degree. C. (2 weeks and 1 month)
using a temperature and humidity test chamber (LH2O-12M; Nagano
Science), and then related substances were measured by HPLC under
the following conditions.
<Testing Conditions>
Column: Waters Atlantis dC18, 5 .mu.m, 4.6.times.250 mm Column
temperature: maintained constant at about 35.degree. C. Injection
volume: 5 .mu.L Detector: UV absorption photometer (Measured
wavelength: 210 nm) Mobile phase A: 1.32 g of diammonium hydrogen
phosphate was dissolved into 900 mL of water, to which was added
phosphoric acid to adjust the pH to 3.0, and the total volume was
adjusted to 1000 mL with water. Mobile phase B: acetonitrile for
liquid chromatography Gradient program: The mixing ratio of mobile
phases A and B was controlled to change in the following
manner.
TABLE-US-00002 Time after Mobile phase Mobile phase injection (min)
A (vol %) B (vol %) 0-5 100 0 5-20 100 .fwdarw. 90 0 .fwdarw. 10
20-30 90 10
Flow rate: 1.0 mL/min Retention time of compound (I): Approximately
6.5 min Measurement time: 30 min
Changes in the total amount of related substances for each sample
were shown in Table 2. The crystalline lyophilized compositions
contained lower amounts of related substances in the initial state
than the amorphous lyophilized composition. Moreover, there was,
after the stress tests, a considerable increase in the amount of
related substances present in the amorphous lyophilized
composition, whereas increases in the amounts of related substances
were lower for the crystalline lyophilized compositions. These
results confirmed that turning compound (I) into a crystalline
lyophilized composition using a method of the present invention
produces a marked improvement in storage stability.
TABLE-US-00003 TABLE 2 Total amount of related substances (%)
60.degree. C. 60.degree. C. Crystallinity Initial state 2 weeks 1
month Example 1a Crystalline 0.25 1.30 0.98 Example 1b Crystalline
0.30 0.50 0.55 Comparative Amorphous 0.56 15.07 24.54 example 1
Reference Example 1
Method for Producing Compound (I)
Reference Example 1a
tert-Butyl{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl-
]carbonyl}amino)oxy]ethyl}carbamate
##STR00003##
A solution of
(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic
acid (4.80 kg, 17.373 mol) in dehydrated ethyl acetate (62 L) was
cooled to -30.degree. C., to which isobutyl chloroformate (2.52 kg)
and then triethylamine (1.85 kg) were added dropwise, and was
stirred at -30.degree. C. for 15 minutes. To the reaction mixture
was added a solution of tert-butyl 2-(aminooxy)ethylcarbamate in
dehydrated ethyl acetate (15 wt %, 23.45 kg) over 30 minutes (the
residue washed with 2 L of dehydrated ethyl acetate), and the
temperature was raised to 0.degree. C. over 1 hour. The mixture was
washed sequentially with an 8% solution of citric acid (65 L), a 5%
solution of sodium bicarbonate (60 L), and water (60 L), and
concentrated to 24 L. A step of adding ethyl acetate (24 L) to the
concentrated mixture, followed by concentration to 24 L for solvent
displacement was performed twice, and to the resultant concentrated
solution, ethyl acetate (29 L) and hexane (72 L) were added, and
stirred overnight. To the mixture, hexane (82 L) was added dropwise
and stirred for 2 hours. The precipitated crystals were separated
by filtration, washed with hexane, and vacuum-dried to give 5.51 kg
of the title compound (yield 76%).
HPLC:COSMOSIL 5C18 MS-II 4.6.times.150 mm, 33.3 mM phosphate
buffer/MeCN=50/50, 1.0 mL/min, UV 210 nm, RT 4.4 min; .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 1.44 (s, 9H), 1.56-1.70 (m, 1H),
1.90-2.09 (m, 2H), 2.25-2.38 (m, 1H), 2.76 (d, J=11.6 Hz, 1H), 3.03
(br. d., J=11.6 Hz, 1H), 3.24-3.47 (m, 3H), 3.84-4.01 (m, 3H), 4.90
(d, J=11.6 Hz, 1H), 5.05 (d, J=11.6 Hz, 1H), 5.44 (br. s., 1H),
7.34-7.48 (m, 5H), 9.37 (br. s., 1H); MS m/z 435 [M+H].sup.+.
Reference Example 1b
tert-Butyl
{2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]-
carbonyl}amino)oxy]ethyl}carbamate
##STR00004##
To a solution of tert-butyl
{2-[({[(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl-
}amino)oxy]ethyl}carbamate (5.52 kg, 12.705 mol) in methanol (85
L), a 10% palladium-carbon catalyst (50% water, 0.55 kg) was added
and stirred under hydrogen pressure (0.1 MPa) for 1 hour. The
catalyst was filtered off and the solid was washed with methanol
(25 L). The filtrate and wash were combined and concentrated under
reduced pressure to 39 L at a solution temperature below 10.degree.
C. A step of adding acetonitrile (44 L) to the concentrated
mixture, followed by concentration to 39 L at a solution
temperature below 10.degree. C. for solvent displacement was
performed twice, and the mixture was cooled to 0.degree. C. and
stirred overnight. The precipitated crystals were separated by
filtration, washed with acetonitrile (24 L), and vacuum-dried to
give 3.63 kg of the title compound (yield 83%).
HPLC:COSMOSIL 5C18 MS-II 4.6.times.150 mm, 33.3 mM phosphate
buffer/MeCN=75/25, 1.0 mL/min, UV 210 nm, RT 3.9 min; .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 1.44 (s, 9H), 1.73-1.83 (m, 1H),
1.86-1.99 (m, 1H), 2.01-2.12 (m, 1H), 2.22 (br. dd., J=15.0, 7.0
Hz, 1H), 3.03 (d, J=12.0 Hz, 1H), 3.12 (br. d., J=12.0 Hz, 1H),
3.25-3.35 (m, 2H), 3.68-3.71 (m, 1H), 3.82-3.91 (m, 3H); MS m/z 345
[M+H].sup.+.
Reference Example 1c
Tetrabutylammonium tert-butyl
{2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbony-
l}amino)oxy]ethyl}carbamate
##STR00005##
To acetonitrile (51 L) were sequentially added water (51 mL),
tert-butyl
{2-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}a-
mino)oxy]ethyl}carbamate (3.53 kg, 10.251 mol), sulfur
trioxide-pyridine complex (3.95 kg), and 2,6-lutidine (2.21 kg),
and stirred at 35 to 45.degree. C. overnight. The mixture was
filtered to remove the insoluble matter, the solid was washed with
acetonitrile (11 L) and the filtrate and wash were combined and
concentrated to 17 L. The concentrated solution was cooled to below
10.degree. C., to which were added a 9% aqueous solution of sodium
dihydrogenphosphate (60 L) and ethyl acetate (113 L) to effect
phase separation, and the organic layer was extracted again with a
9% aqueous solution of sodium dihydrogenphosphate (11 L). To the
aqueous layer obtained were added ethyl acetate (113 L), a 30%
aqueous solution of tetrabutylammonium hydrogen sulfate (12.87 kg),
and a 37% aqueous solution of sodium dihydrogenphosphate (56.5 kg),
and stirred for 15 minutes. The organic layer was separated, washed
with a 20% aqueous solution of sodium dihydrogenphosphate (60 L),
dried over anhydrous magnesium sulfate (2.5 kg), filtered, and then
concentrated under reduced pressure. Crystals of the title compound
deposited in the concentrated solution were dissolved into ethyl
acetate, and the total volume was adjusted to 20 L to yield 32.55
kg of a solution of the title compound in ethyl acetate (net 6.25
kg, yield 92%). This solution was used in the next step without
further purification.
Reference Example 1d
Crude Compound (I)
##STR00006##
A solution of tetrabutylammonium tert-butyl
{2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbony-
l}amino)oxy]ethyl}carbamate (788 g, net 467.1 g, 0.701 mol) in
dichloromethane (934 mL) was cooled to -20.degree. C. in a nitrogen
stream, to which trifluoroacetic acid (934 mL) was added dropwise
over 15 minutes, and the temperature was raised to 0.degree. C.,
followed by stirring for 1 hour. The reaction mixture was cooled to
-20.degree. C., to which diisopropyl ether (4.17 L) was added
dropwise, after which the temperature of the mixture was raised to
-6.degree. C., followed by stirring for 1 hour. The precipitate was
filtered, washed by suspension in diisopropyl ether (2.times.1 L),
and the wet solid was vacuum-dried to give 342.08 g of the title
compound (net 222.35 g, yield 98%, HPLC area ratio 96.1%, CE/TFA 27
mol %).
Reference Example 1e
0.2 M phosphate buffer (pH 6.5, 7.2 L) was cooled to below
10.degree. C., to which
(2S,5R)--N-(2-aminoethoxy)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3-
.2.1]octane-2-carboxamide (the crude compound (I) in Reference
example 1d, net 1.2 kg) and ice-cold 0.2 M phosphate buffer (pH
6.5, 3.5 L) were added alternately portionwise while stirring in a
manner in which the pH remained between 4.2 and 4.8, and the final
pH was adjusted to 4.6. The mixture was diluted with water (19.3 L)
(total quantity 30 L), and concentrated to 24 L under reduced
pressure at solution temperatures below 18.degree. C. After the pH
of the concentrated solution was adjusted to 5.4 with 0.2 M
phosphate buffer (pH 6.5, 2.4 L), the concentrated solution was
diluted with water to 43.2 L and purified using a resin (Sepabeads
SP207, 75 L), where water (83 L) and a 10% aqueous solution of
isopropanol were used for elution and active fractions were
collected. The active fractions were combined (33 L), concentrated
to 7.2 L at solution temperatures below 15.degree. C., to which was
added activated carbon (24 g), followed by stirring for 30 minutes.
The activated carbon was filtered off through a membrane filter,
and washed with water (0.4 L.times.2). The filtrate and wash were
combined and after the temperature of the solution was adjusted to
20 to 25.degree. C., crystalline form III (3.6 g) obtained
according to a method mentioned in Example 7a of Patent Document 6
were inoculated. To the mixture, isopropanol (50.4 L) was added
dropwise over 1 hour, and stirred overnight. The crystals deposited
were filtered, washed with isopropanol (4.8 L) and vacuum-dried
until the temperature of the wet crystals reached 20.degree. C., to
yield 1.17 kg of crystalline form III of compound (I) (yield
90%).
INDUSTRIAL APPLICABILITY
According to the present invention, crystals, especially a single
crystalline form, and in particular stable crystalline form I of
compound (I) can be produced easily in an industrial scale, and
further the present invention provides a lyophilized composition of
compound (I), and especially a single crystalline form and in
particular crystalline form I thereof, having good storage
stability and therefore provides a useful method for producing
injections and the like of compound (I).
* * * * *
References